1998); however, all published MRI studies of inhibited temperament have been conducted in adolescents and young adults (see Figure 5). Thus, no studies to date have been able to address two important questions: Do inhibited children show differences in brain structure or function? What are the developmental trajectories of brain structure and function in inhibited children? Future studies are needed to elucidate the early brain endophentoype of inhibited temperament, especially before the onset of psychopathology. Develop anxiety risk profiles using combined imaging, genetics, behavioral, and psychophysiological measures. Another critical future direction is to understand why children with early inhibited temperament have divergent outcomes, given about 44 of inhibited children go on to develop social anxiety disorder by adolescence (see Figure 1; Clauss and Blackford, 2012), whereas more than half of inhibited children go on to be GW9662 web healthy adults. To date, there are noAuthor Manuscript Author Manuscript Author Manuscript Author Manuscript2.3.Prog Neurobiol. Author manuscript; available in PMC 2016 April 01.Clauss et al.Pagespecific genetic or neural biomarkers to predict which inhibited children will go on to develop anxiety disorders (for a discussion, see: Henderson et al., 2014). We recommend a large scale, multi-site study that combines multiple measures across several system levels (genes, brain, physiology, behavior), as well as environment (e.g., parenting, parent psychopathology), to provide a comprehensive assessment of the phenotype. These data could then be analyzed using cluster analyses or machine learning to identify the combination of measures that are most predictive of later psychopathology. This type of approach can provide valid risk models that can lead to targeted prevention interventions to the BMS-214662 biological activity highest-risk children. 4. Conduct a large-scale multi-site genome-wide association study (GWAS) of inhibited temperament. GWAS studies have the potential to uncover novel biological mechanisms that underlie inhibited temperament and guide future research and development of prevention strategies for the highest-risk children. Significant advances have been made in several psychiatric disorders using large scale GWAS studies based on consortia that combine data across many sites (Cross-Disorder Group of the Psychiatric Genomics Consortium, 2013; Ripke et al., 2011; Visscher et al., 2012). However, to date, most genetic studies of inhibited temperament have used candidate gene approaches with relatively small sample sizes. While these have been informative and have provided preliminary evidence for a genetic basis of inhibited temperament, this approach is limited to known candidate genes. GWAS studies of inhibited temperament have the potential to broaden our knowledge of the genetics of inhibited temperament from the “usual suspects” and to identify novel genes previously not associated inhibited temperament. Test for neurobiological differences in children with an uninhibited temperament. Inhibited temperament has been the main focus of studies of temperament given its association with anxiety disorders and depression; however, uninhibited temperament is also associated with psychopathology, including attention deficit hyperactivity disorder (ADHD), bipolar disorder, and substance use disorders (Hirshfeld-Becker et al., 2007, 2003, 2002). Much remains unknown about the genetic and neural basis of uninhibited temperament and.1998); however, all published MRI studies of inhibited temperament have been conducted in adolescents and young adults (see Figure 5). Thus, no studies to date have been able to address two important questions: Do inhibited children show differences in brain structure or function? What are the developmental trajectories of brain structure and function in inhibited children? Future studies are needed to elucidate the early brain endophentoype of inhibited temperament, especially before the onset of psychopathology. Develop anxiety risk profiles using combined imaging, genetics, behavioral, and psychophysiological measures. Another critical future direction is to understand why children with early inhibited temperament have divergent outcomes, given about 44 of inhibited children go on to develop social anxiety disorder by adolescence (see Figure 1; Clauss and Blackford, 2012), whereas more than half of inhibited children go on to be healthy adults. To date, there are noAuthor Manuscript Author Manuscript Author Manuscript Author Manuscript2.3.Prog Neurobiol. Author manuscript; available in PMC 2016 April 01.Clauss et al.Pagespecific genetic or neural biomarkers to predict which inhibited children will go on to develop anxiety disorders (for a discussion, see: Henderson et al., 2014). We recommend a large scale, multi-site study that combines multiple measures across several system levels (genes, brain, physiology, behavior), as well as environment (e.g., parenting, parent psychopathology), to provide a comprehensive assessment of the phenotype. These data could then be analyzed using cluster analyses or machine learning to identify the combination of measures that are most predictive of later psychopathology. This type of approach can provide valid risk models that can lead to targeted prevention interventions to the highest-risk children. 4. Conduct a large-scale multi-site genome-wide association study (GWAS) of inhibited temperament. GWAS studies have the potential to uncover novel biological mechanisms that underlie inhibited temperament and guide future research and development of prevention strategies for the highest-risk children. Significant advances have been made in several psychiatric disorders using large scale GWAS studies based on consortia that combine data across many sites (Cross-Disorder Group of the Psychiatric Genomics Consortium, 2013; Ripke et al., 2011; Visscher et al., 2012). However, to date, most genetic studies of inhibited temperament have used candidate gene approaches with relatively small sample sizes. While these have been informative and have provided preliminary evidence for a genetic basis of inhibited temperament, this approach is limited to known candidate genes. GWAS studies of inhibited temperament have the potential to broaden our knowledge of the genetics of inhibited temperament from the “usual suspects” and to identify novel genes previously not associated inhibited temperament. Test for neurobiological differences in children with an uninhibited temperament. Inhibited temperament has been the main focus of studies of temperament given its association with anxiety disorders and depression; however, uninhibited temperament is also associated with psychopathology, including attention deficit hyperactivity disorder (ADHD), bipolar disorder, and substance use disorders (Hirshfeld-Becker et al., 2007, 2003, 2002). Much remains unknown about the genetic and neural basis of uninhibited temperament and.
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